Prevalence estimates in the United States for self-injurious behavior (SIB) associated with intellectual and developmental disabilities (IDDs) range from 10 ? 50%. SIB in the IDD population manifests as a wide range of topographies, such as self-directed slapping and head-banging. A subgroup of these patients demonstrates extremely high frequency, high intensity, staccato-like involuntary SIB that has devastating consequences for the patient and their family. Such behaviors are not associated with secondary gain and resemble a stereotyped movement disorder. Stereotyped movement disorders or stereotypies can be a feature of catatonia. Moreover, whilst catatonia is classically associated with mood and psychotic disorders, it is increasingly recognized as comorbid with autism spectrum disorder, and many of these patients also demonstrate more classical akinetic motor signs, characteristic of catatonic states associated with mood disorders or schizophrenia. Consistent with the sensitivity of catatonia to electroconvulsive therapy (ECT), we and others have found ECT can produce life-changing results in IDD patients with extreme SIB that is unresponsive to conventional pharmacological and behavioral therapies. However, these patients typically require frequent maintenance ECT (M-ECT) to sustain the improvement gained during the acute course and the long-term consequences of such frequent M-ECT are unknown. Accordingly, there is a need to develop alternate non-convulsive forms of chronic stimulation for these patients. To evaluate the feasibility of deep brain stimulation for SIB associated with IDDs, we have utilized two mouse models, namely the Viaat-Mecp2-/y and Shank3B-/- lines, that demonstrate stereotyped excessive self- grooming. We found that high frequency stimulation administered via implanted electrodes at the subthalamic nucleus (STN-HFS) significantly suppressed excessive self-grooming. Suppression starts acutely when stimulation is switched on and persists for several days after HFS is stopped. Since STN-HFS stimulates both neurons at the STN and fibers of passage that pass adjacent to this nucleus it is unclear which pathways mediate the acute and persistent suppression of excessive self-grooming by STN-HFS. As it would be important to distinguish between these two mechanisms before considering invasive or non-invasive neuromodulation for patients, we propose employing an optogenetics-based approach to help determine which pathways mediate the response. Specifically, we plan to: Aim 1: Determine if optogenetic stimulation of STN neurons suppresses excessive self-grooming in the Shank3B-/- and Viaat-mecp2-/y mouse models of self-injurious behavior. Aim 2: Determine if optogenetic stimulation of fibers of passage at the STN suppresses excessive self-grooming in the Shank3B-/- and Viaat-mecp2-/y mouse models of self- injurious behavior.